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NEWS OFTHE WEEK

NOBEL PRIZE IN CHEMISTRY Two biochemists win for DNA work

The 1993 Nobel Prize in Chemis­try was awarded last week to two biochemists whose develop­

ment of chemical methods for manipu­lating DNA has revolutionized genetic engineering, stimulated basic biochem­ical research, and opened the door for new applications in industry and med­icine. The $825,000 prize'will be shared by American Kary B. Mullis, who now works as a private consultant and writ­er in La Jolla, Calif., and British-born Canadian Michael Smith, a biochemis­try professor and director of the Bio­technology Laboratory at the Universi­ty of British Columbia, Vancouver.

Another pair of researchers who made a fundamental discovery in genetic struc­ture received the 1993 Nobel Prize in Physiology or Medicine (see next article).

And the Nobel Prize in Physics went to Russell A. Hulse and Joseph H. Taylor Jr., both of Princeton University, for their discovery of the first binary pulsar, which has opened up new possibilities for testing theories of gravitation.

Mullis, 48, won the chemistry prize for inventing the polymerase chain re­action (PCR), a simple method for making billions of copies of a specific gene sequence in a few hours. Smith, 61, was cited by the Royal Swedish Academy of Sciences for "his funda­mental contributions to the establish­ment of oligonucleotide-based site-directed mutagenesis and its develop­ment for protein studies/'

Mullis devised the PCR method in 1983 while he was working at Cetus Corp. in Emeryville, Calif. In the decade since, the method has become an essen­tial tool in molecular biology laborato­ries for increasing the amount of a gene sequence available for study. This year, the public became aware of it when PCR played a crucial role in the plot of the blockbuster film Jurassic Park."

PCR has become invaluable for diag­nosing diseases and detecting pathogens in the body. For example, PCR is now the definitive way to detect the AIDS virus

Mullis (above), returning from surfing, and Smith, receiving congratulations

hiding in a patient's cells. And because PCR requires only a single hair or drop of blood to identify an individual, it has proved to be a boon in forensic investiga­tions. The method also has made it much easier to determine genetic and evolution­ary connections between different species. And without PCR, undertaking the hu­man genome project "would hardly be realistic," says the Swedish academy.

Smith's work on site-directed mu­tagenesis has made it possible to repro-gram the genetic code that determines the identity and sequence of amino acids in a protein. The method allows one to change the base at one site on the DNA strand, thus altering the coding for a particular amino acid at a particular po­sition in the protein to be constructed. It is thus possible to replace specific amino acids in a protein and to construct mu­tant proteins with new properties.

Among the many applications of Smith's technique is the design of anti­bodies that will neutralize cancer cells and the alteration of plant proteins to create crop strains with a variety of new traits. In the future, the Swedish

academy suggests, Smith's fundamen­tal contributions may allow hereditary diseases to be cured by correcting the underlying genetic defect. Both Smith's work and the PCR method also offer great potential for gene therapy.

Smith began work on the idea of site-directed mutagenesis in the early 1970s. But it took him and his cowork­ers about a decade before they succeed-

6 OCTOBER Ί8. Ί993 C&EN

Page 2: NOBEL PRIZE IN CHEMISTRY

ed in making and isolating large quan­tities of a mutated enzyme in which a predetermined amino acid had been exchanged for another one.

The gestation period of Mullis' PCR idea also had its difficulties. According to an article that appeared last week in the Sunday newspaper supplement Pa­rade, which portrayed him as an uncon­ventional scientist who likes rollerblad-ing and surfing, Mullis' idea at first received a frosty reception from his col­leagues at Cetus, and he had trouble pub­lishing his findings. In any case, three days before last week's chemistry Nobe-lists were named, the publication suggest­ed that Mullis could win the prize.

Ron Dagani

/Split genes' discovery wins medicine Nobel Two U.S. researchers who were educat­ed as chemists won the 1993 Nobel Prize in Physiology or Medicine last week for their discovery that genes can consist of two or more well-separated segments of genetic material (DNA).

British-born Richard J. Roberts and American-born Phillip A. Sharp share the $842,000 prize for their independent discovery in 1977 of "split genes." Rob­erts, 50, is a research director at New England Biolabs, a company in Beverly, Mass., that makes restriction enzymes and related products for molecular biol­ogy research. Sharp, 49, is a cancer re­searcher who heads the biology depart­ment at Massachusetts Institute of Tech­nology. Both men earned bachelor's and doctorate degrees in chemistry.

"The discovery of split genes has been of fundamental importance for today's basic research in biology, as well as for more medically oriented research [on] the development of cancer and other diseases," says Stockholm's Karolinska Institute, which awarded the prize.

Before 1977, scientists envisioned a gene as a single segment of double-stranded DNA. The gene's information, they had discovered, is copied into a sin­gle-stranded RNA molecule (messenger RNA), which then translates this coded message into a protein.

This simple picture was shattered when Roberts and Sharp found a viral gene that exists as four discrete, well-separated segments of DNA. These gene segments, now known as exons, are sep­

arated by introns—so-called nonsense DNA because it apparently bears no protein-coding message. Very soon after this discovery, other researchers showed that such split genes are common—in fact, the most common gene structure in higher organisms.

"This knowledge has radically changed our view of how genetic material has de­veloped during the course of evolution," says the Karolinska Institute. Scientists have long thought that evolution takes place gradually as the result of the accu­mulation of minor alterations in DNA. Now, says Sharp, scientists know that new genetic variations also can arise through the shuffling of gene segments.

The discovery of split genes revealed the existence of RNA splicing: After a multisegment gene is copied onto mes­senger RNA, the RNA strand is "edit­ed" to remove the introns. The remain­ing exons are joined together to form a shortened RNA strand that duplicates the information in the gene. The trimmed messenger RNA leaves the cell nucleus and goes to the ribosomes in the main body of the cell, where the RNA serves as a blueprint for protein assembly.

The importance of splicing became apparent when researchers discovered that exons of the same gene can be used in different combinations to code for different proteins. They also learned that an exon for one protein can be treated as an intron (and thus is snipped out) when the cell's machinery wants to make a different protein. Likewise, in­trons can become exons for particular proteins. Thus, the DNA instructions themselves do not necessarily specify a specific protein when they are copied into RNA. Rather, it is the splicing pat­tern—what is snipped out and what

Roberts (left) and Sharp independently discovered 'split genes' in 1977

isn't—that determines the nature of the final protein.

Recent research suggests that this splic­ing process can go awry, leading to cer­tain hereditary diseases. These include muscular dystrophy, beta-thalassemia (a type of anemia), and chronic myelocytic leukemia (a type of cancer of the blood).

Ultimately, the discovery by Roberts and Sharp could lead to improvements in gene therapy and to a better under­standing of the cause of cancer, says Gosta Gahrton, a member of the Karo­linska Institute.

Ron Dagani

Hoechst Celanese pays premium for drug firm Hoechst Celanese plans to buy 51% of generic drugmaker Copley Pharmaceu­tical for $546 million. Hoechst Celanese will pay a premium for the Canton, Mass.-based generic drug manufactur­er, hoping to position itself for growth in the drug industry.

Critics expressed amazement that Hoechst Celanese would pay so much for Copley considering the generic drug maker's sales in 1992 were only $52 mil­lion. In contrast, Marion Merrell Dow just paid $275 million for generic drug company Rugby Darby, or about the same as Rugby's 1992 sales. And Merck plans to buy generic distributor Medco Containment for $6 billion, or about three times Medco's 1992 sales.

A Hoechst Celanese spokesman points

OCTOBER 18, 1993 C&EN 7